Divergent Synthesis of Natural Derivatives of (+)-Saxitoxin Including 11-Saxitoxinethanoic Acid

Article abstract of DOI:10.1002/anie.201811717

The bis-guanidinium toxins are a collection of natural products that display nanomolar potency against select isoforms of eukaryotic voltage-gated Na⁺ ion channels. We describe a synthetic strategy that enables access to four of these poisons, namely 11-saxitoxinethanoic acid, C13-acetoxy saxitoxin, decarbamoyl saxitoxin, and saxitoxin. Highlights of this work include an unusual Mislow–Evans rearrangement and a late-stage Stille ketene acetal coupling. The IC₅₀ value of 11-saxitoxinethanoic acid was measured against rat Na_V1.4, and found to be 17.0 nm, similar to those of the sulfated toxins gonyautoxin II and III.

Full text of DOI:10.1002/anie.201811717

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Divergent Synthesis of Natural Derivatives of (+)-Saxitoxin
Including 11-Saxitoxinethanoic Acid
Authors: James R Walker, Jeffrey E Merit, Rhiannon Thomas-Tran,
Doris T. Y. Tang, and Justin Du Bois
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201811717
Angew. Chem. 10.1002/ange.201811717
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10.1002/anie.201811717
Angewandte Chemie International Edition
COMMUNICATION
Divergent Synthesis of Natural Derivatives of (+)-Saxitoxin Including
11-Saxitoxinethanoic Acid
James R. Walker[b],‡, Jeffrey E. Merit[c],‡, Rhiannon Thomas-Tran[d], Doris T. Y. Tang[a], J. Du Bois[a]*
‡These authors contributed equally to this work
Abstract: The bis-guanidinium toxins are a collection of natural
HO
11
–O3SO
HO
O
N
NH2
O
NH2
O
products that display nanomolar potency against select isoforms of
eukaryotic voltage-gated Na+ ion channels. We describe a synthetic
strategy that enables access to four of these poisons, including 11-
saxitoxinethanoic acid, C13-acetoxy saxitoxin, decarbamoyl-
saxitoxin, and saxitoxin. Highlights of this work include an unusual
Mislow-Evans rearrangement and a late-stage Stille ketene acetal
coupling. The IC50 of 11-saxitoxinethanoic acid has been measured
against rat NaV1.4, and found to be 17.0 nM, similar to sulfated
toxins gonyautoxin II and III.
O
NH2
N
NH2
N
O
O
NH2
HO
HO
HO
11
NH
NH
N
N
H
–O2C
OH
NH
HO
HN
HN
HN
HO
NH
NH
N
O
H2N
H2N
H2N
O
(+)-saxitoxin (STX)
11-saxitoxin-
ethanoic acid (SEA)
zetekitoxin AB (ZTX)
Figure 1. Selected bis-guanidinium natural products.
A number of synthetic routes to bis-guanidinium toxins have
been delineated, including a recent effort by Nagasawa and
coworkers to prepare SEA.[5,6,7] For our purposes, we desired a
synthesis of C11-modified toxins that would allow for
introduction of the C11 group on an advanced intermediate,
thereby facilitating access to SEA, ZTX, and related analogues.
Cross-coupling of an appropriate nucleophilic partner with α-
iodoenaminone 2 was envisioned as a solution to this problem
(Scheme 1). This substrate would be available through oxidation
of allylic alcohol 3 followed by α-halogenation. Access to 3 could
be achieved by rearrangement of N,O-acetal 4, an intermediate
obtained from pyrrole 5 by way of a Pictet-Spengler reaction.[5a,b]
The bis-guanidinium toxins, as exemplified by saxitoxin (STX,
Figure 1), are a distinct collection of natural products that target
voltage-gated sodium channels (NaVs).[1] Structural variations
among STX congeners occur primarily at two positions, C11 and
C13.[2] Although most C11-modified toxins are oxidized at this
site, among the 57 known natural STX derivatives, 11-
saxitoxinethanoic acid (SEA) and zetekitoxin AB (ZTX) are the
only two that bear C11-carbon substituents. Little is known about
the potency, NaV isoform selectivity, and toxicity of SEA;[3] the
more complex agent, ZTX, is reported to display sub-nanomolar
IC50 against three NaV subtypes.[4] The lack of material from
natural sources restricts further investigations of either molecule.
Inspired by the synthetic challenges presented by SEA and ZTX
as well as questions regarding the influence of C11-substitution
on toxin binding to NaVs, we initiated efforts to prepare these
unique isolates. Herein, we report a divergent strategy for
asymmetric synthesis of SEA and three additional toxin natural
products.
NH2
H2N +
TcesN
TcesN
NH
O
O
NH OR
NH
NH OR
NH
HO
HO
HN
12
N
HN
HN
O
O
I
NH
11
N
N
–O2C
EtO2C
+
NH2
NTroc
NTroc
SEA
1
2
TcesN
HN
TcesN
OSitBuPh2
O
NH OR
NH
NH OR
NH
HN
HO
N
NH
N
N
AcO
O
NTroc
NTroc
5
4
3
[a]
Doris T. Y. Tang and J. Du Bois
Department of Chemistry
Stanford University
Stanford, CA 94305
E-mail: jdubois@stanford.edu
James R. Walker
SAFC, Inc.
645 Science Dr.
Madison, WI 53711
Jeffrey E. Merit
Gilead Sciences
Scheme 1. Retrosynthetic analysis of 11-saxitoxinethanoic acid (SEA). Tces =
2,2,2-trichloroethoxysulfonyl, Troc
SitBuPh2.
=
2,2,2-trichloroethoxycarbonyl,
R
=
[b]
[c]
[d]
The assembly of N,O-acetal 4 from L-serine methyl ester is
possible on multigram scales using a well-established process
developed in our lab.[5a,b] The N,O-acetal is susceptible to
reduction under conditions that employ a Lewis acid and
trialkylsilane. Other nucleophiles exchange with 4 quite readily,
including PhSH to give the corresponding N,S-acetal 6 (Scheme
2).[8,9] In order to introduce the requisite oxygenation at C12, a
structural feature common to all bis-guandinium toxins, a plan
involving Mislow-Evans [2,3]-rearrangement of sulfoxide 7 was
conceived. The stability of this unusual acetal and limited
precedent for such a sequence of steps, however, raised
questions about the viability of this idea.[9] These issues
notwithstanding, selective oxidation of 6 proceeded without
event and afforded the desired sulfoxide 7 as a stable, 1:1
mixture of diastereomers.[10]
333 Lakeside Dr.
Foster City, CA 94404
Rhiannon Thomas-Tran
Arcus Biosciences, Inc.
3928 Point Eden Way
Hayward, CA 94545
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201811717
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COMMUNICATION
TcesN
TcesN
HN
TcesN
HN
(CDI) and NH3 (Scheme 4). Esterification of 9 also proceeded
smoothly with acetyl cyanide to give the corresponding acetate
ester 10. Upon removal of the Tces- and Troc-groups from these
intermediates, STX and C13-acetoxy STX were obtained. The
latter is a natural congener of STX produced by the freshwater
cyanobacterium Lyngba wollei, and to our knowledge has not
been prepared previously.[14, 15]
NH OR
NH OR
NH
NH OR
NH
HN
12
a
b
N
NH
N
N
+
–O
S
AcO
PhS
NTroc
: R = SitBuPh2
NTroc
NTroc
Ph
4
6
7
Scheme 2. Sulfoxide synthesis from N,O-acetal 4. Reagents and conditions:
TcesN
TcesN
TcesN
(a) PhSH, BF3•OEt2, CH2Cl2, 84%; (b) urea•H2O2, HFIP, 88%. HFIP
hexafluoro-2-propanol.
=
NH OR
NH OR
NH
NH OH
NH
HN
HN
HN
O
HO
O
a
b,c
Initial attempts to effect [2,3]-rearrangement of sulfoxide 7 using
conventional conditions (P(OMe)3, MeOH, 65 °C) surprisingly
returned starting material (entry 1, Table 1). Switching to EtOH
solvent and heating the reaction to 80 °C resulted in formation of
the corresponding allylic alcohol product, albeit in modest yield
(42%, entry 2). In addition, exchange of the Troc-protecting
group to an ethyl carbamate was also noted. Use of 2,2,2-
trichloroethanol as solvent rendered the exchange reaction
redundant; however, the product was not easily separated from
P(OMe)3 (entry 3). After screening alternative reductants,
sodium thiophenolate was identified as an optimal additive (entry
4). When employed in combination with trichloroethanol, the
desired alcohol 3 was obtained in 89% yield. Accordingly,
conversion of N,O-acetal 4 to this compound follows an efficient
three-step sequence, giving access to a particularly versatile
intermediate for preparing toxin derivatives.
N
NH
N
N
NTroc
NTroc
NTroc
3: R = SitBuPh2
8
9
Scheme 3. Synthesis of the fully elaborated bis-guanidine toxin core.
Reagents and conditions: (a) Dess-Martin periodinane, CH2Cl2, 95%; (b) 25
mol % [Ir(cod)(PCy3)(py)]PF6, B(OiPr)3, 500 psi H2, CH2Cl2, 75%; (c) n-Bu4NF,
AcOH, THF, −78–23 °C, 86%.
NH2
H2N +
TcesN
H2N +
NH OH
NH OH
NH
NH
O
O
HO
HO
HN
HN
HN
O
a
b,a
HO
HO
N
NH
N
N
NH
+
+
NH2
NTroc
NH2
dc-STX
9
STX
CH3
CH3
O
TcesN
TcesN
H2N +
Table 1. Evaluating reaction conditions for Mislow-Evans [2,3]-rearrangement.
NH OH
NH
NH
O
O
NH
O
HO
HN
HN
HN
O
O
c
a
HO
TcesN
HN
TcesN
N
N
NH
N
NH
NH
NH
HN
HO
OSitBuPh2
OSitBuPh2
+
conditions
NTroc
NTroc
10
NH2
N
NH
N
NH
C13-acetoxy STX
9
+
–O
NC(O)R
S
NTroc
Scheme 4. Access to three bis-guanidinium toxin natural products from a
common precursor 9. Reagents and conditions: (a) 1 atm H2, PdCl2, CF3CO2H,
MeOH/H2O, 14–46%. (b) 1,1’-carbonyldiimidazole, THF; then 0.5 M NH3 in
THF, 69%; (c) CH3C(O)CN, DMAP, CH2Cl2, 64%.
Ph
7
Entry
Conditions
R
%Yield
NR
1
2
3
4
P(OMe)3, MeOH, 65 °C
P(OMe)3, EtOH, 80 °C
–
Turning our focus towards the synthesis of C11-substituted bis-
guanidinium toxins, SEA and ZTX, we investigated methods for
C11-functionalization of enaminone 8. Our inability to identify
suitable conditions for conjugate hydride addition precluded a
tandem 1,4-reduction/enolate alkylation sequence. Thus, we
became interested in Baylis-Hillman-type processes to introduce
an alkyl group at C11. Although we were unsuccessful in
developing such a protocol, it was possible to transform 8 into
OEt
42
P(OMe)3, Cl3CCH2OH, 80 °C
NaSPh, Cl3CCH2OH, 80 °C
OCH2CCl3
80
OCH2CCl3
89
Oxidation of alcohol 3 with Dess-Martin periodinane afforded
enaminone 8 in 95% yield (Scheme 3). With this compound, it is
possible to synthesize decarbamoyl STX (dc-STX), STX, and
C13-acetoxy-STX. The sequence to all three natural products
involves enaminone 1,4-reduction and C13-desilylation to
generate a protected form of dc-STX (9). Conjugate reduction of
8 was first attempted using different Cu-hydride sources, but
these conditions generally resulted in Troc-deprotection without
concomitant reduction of the C10,C11-alkene.[11] Of the many
methods and protocols tested, hydrogenation with catalytic
[Ir(cod)(PCy3)(py)]PF6 in combination with B(OiPr)3, a critical
additive for promoting catalyst turnover, proved uniquely
successful and furnished the saturated ketone in 75% yield.[12]
Following desilylation of this material with acetic acid-buffered
tetrabutylammonium fluoride to give 9, removal of the two
guanidine protecting groups under hydrogenolytic conditions (H2,
cat. PdCl2) gave dc-STX (Scheme 4).
the α-iodinated product using I2 and pyridine (Scheme 5).[16] We
speculate based on literature precedent that this reaction occurs
through reversible formation of a pyridinium adduct.[17] Under
these conditions, the iodinated product was isolated in 66% yield.
TcesN
TcesN
–O
NH OR
NH OR
NH
HN
HN
O
O
I2, pyridine
N
I
N
NH
N
+
N
CH2Cl2
NTroc
: R = SitBuPh2
NTroc
66%
8
2
Scheme 5. Selective α-iodination of enaminone 8.
To complete a synthesis of SEA, cross-coupling reactions of 2
with primary ester enolate or suitable equivalent were
examined. Exposure of this substrate to reagents such as the
zinc enolate of ethyl acetate and Pd(0) sources, however,
resulted in unproductive consumption of starting material (entry
1, Table 2).[18,19,20,21,22] Iodoenaminone 2 is particularly unstable
To complete a synthesis of STX from 9, carbamoylation of the
alcohol group was first attempted with trichloroacetyl isocyanate;
use of this reagent, however, resulted in competitive guanidine
functionalization.[7c, 13 ] Instead, successful installation of the
carbamate group was possible using 1,1’-carbonyldiimidazole
a
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10.1002/anie.201811717
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COMMUNICATION
to base (including fluoride ion), and thus we were compelled to
explore neutral, Stille-based methods to effect the desired
coupling reaction.[23] Unfortunately, the nBu3Sn-enolate of ethyl
acetate proved unreactive as a cross-coupling partner (entry 2).
Other organostannanes such as tributyl(vinyl)tin fared only
slightly better, affording a trace amount of the desired product
(entry 3). In light of these results, we were surprised to find that
treatment of iodoenaminone 2 with cis-tributyl(2-ethoxyvinyl)tin,
a commercially available acetaldehyde synthon, and 10 mol%
(2.5:1 dr), conditions that do not result in cleavage of either the
Troc- or Tces-groups (Scheme 7). Subsequent desilylation of
15 and installation of the requisite carbamate moiety gave a
protected form of SEA. Finally, hydrogenolytic removal of both
guanidine protecting groups and ethyl ester hydrolysis yielded
the natural product. SEA was obtained as a ~3:1 mixture of C11
epimers, in keeping with the original isolation data and with a
recent disclosure from Nagasawa and coworkers.[6] NMR and
HRMS for the synthetic material agree with the reported
literature values. In addition, pH-dependent D2O exchange is
observed for the C11 hydrogen atom.
25 ]
Pd(PPh3)4 resulted in a productive reaction (entry 4).[ 24 ,
Starting material was fully consumed and the enol ether product
14 (R = cis-(EtO)CH=CH)) was isolated as a fluorescent yellow
compound in 67% yield.[26] These results motivated subsequent
investigation of ketene acetal stannane derivatives as acetate
ester surrogates.
TcesN
TcesN
NH
NH
HN
HN
O
O
b
OSitBuPh2
OSitBuPh2
R
N
NH
NTroc
: R = I
N
NH
11
EtO2C
10
A
method for preparing the novel reagent tributyl(2,2-
NTroc
diethoxyvinyl)tin 13 was devised starting from 1,1,-dibromo-2,2-
diethoxyethane 11 (Scheme 6). Treatment of 11 with KOtBu
effected bromide elimination to give olefin 12. As first
demonstrated in 1937, low temperature lithium-halogen
exchange of this compound is possible without concomitant loss
of LiOEt.[27,28,29] Subsequent trapping of the incipient vinyl anion
with nBu3SnCl afforded 13 in 75% yield.[30]
2
1
15
a
: R = CH2CO2Et
c
NH
NH
H2N+
TcesN
HN
NH
O
HO
HO
HN
O
d,e
O
NH2
OH
N
NH
N
–O2C
EtO2C
+
NH2
NTroc
Table 2. Cross-coupling conditions evaluated with iodoenaminone 2.
saxitoxinethanoic acid
16
Scheme 7. Completed synthesis of 11-saxitoxinethanoic acid. Reagents and
conditions: (a) nBu3SnCH=C(OEt)2, 50 mol% Pd(PPh3)4, CuTC, NMP; then
NH4Cl. 35%; (b) 30 mol% [Ir(cod)(PCy3)(py)]PF6, B(Oi-Pr)3, 500 psi H2, CH2Cl2,
80%, 2.5:1 dr; (c) n-Bu4NF, AcOH, THF, −78–23 °C, 80%; (d) CDI, THF then
0.5 M NH3 in THF, 35%; (e) 1 atm H2, PdCl2, CF3CO2H, MeOH/H2O; then 1.0
M aqueous HCl, 50%. NMP = N-methyl-2-pyrrolidone.
TcesN
TcesN
NH
NH
HN
HN
O
O
conditions
OSitBuPh2
OSitBuPh2
I
R
N
NH
N
NH
NTroc
NTroc
2
14
Successful access to SEA has enabled whole-cell
electrophysiological characterization of this toxin against a
Entry
Nucleophile
Pd cat/ligand
Additive
none
Result
recombinant voltage-gated sodium channel α-subtype. Using
heterologously expressed rat NaV1.4 (CHO cells), the IC50 for
SEA was determined to be 17.0 ± 1.9 nM. Interestingly, the C11-
sulfated toxin, GTX-III, shows comparable potency (14.9 ± 2.1
nM) against this same NaV isoform, despite the fact that SEA is
applied to cells as a ~3:1 mixture of C11-α/β epimers. Given the
lability of the C11-H to solvent exchange, it is possible that toxin
diastereomers are resolved upon binding to the channel and that
t
BrZnCH2CO2 Bu
1
2
3
4
5
6
Pd2(dba)3/dppfa
PdCl2(P(o-tol)3)2
Pd(PPh3)4
decomp.
NR
nBu3SnCH2CO2Et
nBu3SnCH=CH2
CuF2
CuI
< 5%
nBu3SnCH=CH(OEt)
nBu3SnCH=C(OEt)2
nBu3SnCH=C(OEt)2
Pd(PPh3)4
CuCl,LiCl
CuCl,LiCl
CuTC
67%
a
a
Pd(PPh3)4
0-40%b
60%b
a
Pd(PPh3)4
aReaction in THF; bYield determined after ketene acetal hydrolysis with
saturated aqueous NH4Cl. CuTC = Copper(I) thiophene-2-carboxylate.
the β-form is favored. Studies to address this question and to
characterize the action of SEA and related C11-derivatives
against additional NaV isoforms and channel mutants are
ongoing.
KOtBu
tBuLi, THF; then
OEt
OEt
OEt
OEt
OEt
OEt
Br
nBu3SnCl, –78 °C
nBuSn
NH2
O
NH2
O
THF
H2N+
H2N+
Br
11
Br
12
51%
75%
13
NH
O
NH
O
HO
HO
HO
HO
HN
HN
HO
HO
Scheme 6. Preparation of (2,2-diethoxyvinyl)tin 13 for Pd-mediated Stille cross
coupling.
–O3SO
N
NH
N
N
NH
NH2
–O2C
–O2C
+
+
NH2
α-11-SEA
IC50 = 17.0 ± 1.9 (NaV1.4)
Despite the successful coupling reaction of iodoenaminone 2
with cis-tributyl(2-ethoxyvinyl)tin (entry 4, Table 2), the
analogous reaction with 13 delivered the ketene acetal product
in highly variable yields (entry 5). Forced to examine alternative
Pd sources, phosphine ligands, and additives, we identified
Cu(I) thiophene-2-carboxylate (CuTC)[31] as an optimal reagent.
In combination with Pd(PPh3)4 and CuTC, reaction of 2 and 13
reproducibly afforded the vinylated product (entry 6 & Scheme 7).
Mild acid hydrolysis of this material furnished the corresponding
ethyl ester 1 in 60% isolated yield.
(+)-gonyautoxin III
β-11-SEA
IC50 = 14.9 ± 2.1 (NaV1.4)
Figure 2. Comparative potencies of C11-substituted toxins against NaV1.4.
We have successfully prepared four bis-guanidinium toxin
isolates – STX, dcSTX, C13-acetoxy STX, and SEA – through a
divergent sequence that capitalizes on enaminone 8. This
synthetically versatile intermediate was obtained through a
sulfoxide [2,3]-rearrangement, and can be easily processed to
toxins bearing no substitution at C11. The challenge of
assembling 11-saxitoxinethanoic acid required invention of
stannane 13 as a novel ester enolate equivalent and the
development of optimal conditions for cross-coupling this
Synthesis of SEA from 1 was completed following the four-step
sequence used to access STX (vide supra). Initial reduction of
the C10,11-alkene in 1 was achieved with H2 under Ir-catalysis
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10.1002/anie.201811717
Angewandte Chemie International Edition
COMMUNICATION
reagent with iodide 2. All told, the versatile chemistry described
in this report enables access to natural and non-natural toxin-
based probes to support our studies of NaV structure, function,
and physiology.[1,15]
A. Varvoglis, J. A. Callies, V. V. Zhdankin, Tetrahedron Lett. 1997, 38,
8401–8404.
T. Hama, X. Liu, D. A. Culkin, J. F. Hartwig, J. Am. Chem. Soc. 2003,
125, 11176–11177.
[18]
[19]
[20]
W. A. Moradi, S. L. Buchwald, J. Am. Chem. Soc. 2001, 123, 7996–
8002.
Acknowledgements
T. Magauer, J. Mulzer, K. Tiefenbacher, Org. Lett. 2009, 11, 5306–
5309.
We thank Professor Merritt Maduke for generous use of laboratory
space and equipment. J.R.W and R.T-T are grateful to the Center for
Molecular Analysis and Design (CMAD) at Stanford and the National
Science Foundation, respectively, for fellowship awards. This work
has been supported by a grant from the NIH (GM117263-01A1) and
by a gift from Amgen, Inc.
[21] Q. Xiao, W.-W. Ren, Z.-X. Chen, T.-W. Sun, Y. Li, Q-D. Ye, J.-X. Gong,
F.-K. Meng, L. You, Y.-F. Liu, M.-Z. Zhao, L.-M. Xu, Z.-H. Shan, Y. Shi,
Y.-F. Tang, J.-H. Chen, Z. Yang, Angew. Chem. Int. Ed. 2011, 50,
7373–7377.
[22]
[23]
E.-I. Negishi, J. Organomet. Chem. 1999, 576, 179–194.
C. R. Johnson, J. P. Adams, M. P. Braun, C. B. W. Senanayake,
Tetrahedron Lett. 1992, 33, 919–922.
Keywords: guanidinium toxins • sodium channel • sulfoxide
[24]
X. Han, B. Stoltz, E. J. Corey, J. Am. Chem. Soc. 1999, 121, 7600–
rearrangement • Stille coupling
7605
[25]
[26]
A. S. Devlin, J. Du Bois, Chem. Sci. 2013, 4, 1059–1063.
Efforts to manipulate this compound, either by acidic hydrolysis or
oxidation, were unsuccessful, see: J. R. Walker, PhD thesis, Study of
Voltage-Gated Sodium Channels by Mutagenesis, Electrophysiology,
and Synthesis of Novel Toxins Including 11-Saxitoxinethanoic acid,
Stanford University, April 2014.
[1]
[2]
[3]
[4]
A. P. Thottumkara, W. H. Parsons, J. Du Bois, Angew. Chem. Int. Ed.
2014, 53, 5760–5784.
[27]
F. Beyerstedt, S. M. McElvain, J. Am. Chem. Soc. 1937, 59, 2266–
M. Wiese, P. M. D'Agostino, T. K. Mihali, M. C. Moffitt, B. A. Neilan,
2268.
Mar. Drugs 2010, 8, 2185–2211.
[28]
[29]
[30]
[31]
M. Schlosser, H.-X. Wei, Tetrahedron 1997, 53, 1735–1742.
H.-X. Wei, M. Schlosser, Tetrahedron Lett. 1996, 37, 2771–2772.
Yield determined by 1H NMR integration against an internal standard.
O. Arakawa, S. Nishio, T. Noguchi, Y. Shida, Y. Onoue, Toxicon 1995,
33, 1577–1584.
M. Yotsu-Yamashita, Y. H. Kim, S. C. Dudley Jr., G. Choudhary, A.
Pfahnl, Y. Oshima, J. W. Daly, Proc. Natl. Acad. Sci. USA 2004, 101,
4346–4351.
G. D. Allred, L. S. Liebeskind, J. Am. Chem. Soc. 1996, 118, 2748–
2749.
[5]
(a) J. V. Mulcahy, J. Du Bois, J. Am. Chem. Soc. 2008, 130, 12630–
12631; (b) J. V. Mulcahy, J. R. Walker, J. E. Merit, A. Whitehead, J. Du
Bois, J. Am. Chem. Soc. 2016, 138, 5994–6001; (c) O. Iwamoto, K.
Nagasawa, Org. Lett. 2010, 12, 2150–2153.
[6]
[7]
C. Wang, M. Oki, T. Nishikawa, D. Harada, M. Yotsu-Yamashita, K.
Nagasawa, Angew. Chem. Int. Ed. 2016, 55, 11600–1603.
For related studies, see: (a) H. Tanino, T. Nakata, T. Kaneko, Y. Kishi,
J. Am. Chem. Soc. 1977, 99, 2818–2819; (b) P. A. Jacobi, M. J.
Martinelli, P. Slovenko, J. Am. Chem. Soc. 1984, 106, 5594–5598; (c) J.
J. Fleming, M. D. McReynolds, J. Du Bois, J. Am. Chem. Soc. 2007,
129, 9964–9975; (d) O. Iwamoto, R. Shinohara, K. Nagasawa, Chem.
Asian. J. 2009, 4, 277–285; (e) V. R. Bhonde, R. E. Looper, J. Am.
Chem. Soc. 2011, 133, 20172–20174; (f) S. Ueno, A. Nakazaki, T.
Nishikawa, Org. Lett. 2016, 16, 6368–6371, and references therein.
[8]
[9]
D. A. Evans, G. C. Andrews, Acc. Chem. Res. 1974, 7, 147–155.
M. Koprowski, E. Krawczyk, A. Skowroñska, M. McPartlin, N. Choi, S.
Radojevic, Tetrahedron 2001, 57, 1105–1118.
[10]
S. J. Brenek, S. P. Caron, E. Chisowa, M. P. Delude, M. T. Drexler, M.
D. Ewing, R. E. Handfield, N. D. Ide, D. V. Nadkarni, J. D. Nelson, M.
Olivier, H. H. Perfect, J. E. Phillips, J. J. Teixeira, R. M. Weekly, J. P.
Zelina, Org. Process. Res. Dev. 2012, 16, 1348–1359.
[11]
[12]
[13]
[14]
A. I. Meyers, T. R. Elworthy, J. Org. Chem. 1992, 57, 4732–4740.
B. M. Trost, M. T. Rudd, Org. Lett. 2003, 5, 1467–1470.
P. Kocovsky Tetrahedron Lett. 1986, 27, 5521–5524.
H. Onodera, M. Satake, Y. Oshima, T. Yasumoto, W. W. Carmichael,
Nat. Toxins 1997, 5, 146–151.
[15]
[16]
R. Thomas-Tran, J. Du Bois, Proc. Natl. Acad. Sci. USA 2016, 113,
5856–5861.
(a) C. R. Johnson, J. P. Adams, M. P. Braun, C. B. W. Senanayake, P.
M. Wovkulich, M. R. Uskokovic, Tetrahedron Lett. 1992, 33, 917–918.
(b) E. Djuardi, P. Bovonsombat, E. Mc Nelis, Synth. Commun. 1997,
27, 2497–2503.
[17]
An alternative mechanism for formation of the α-iodinated product may
involve direct addition of 8 to an I2•pyridine complex. For related
examples, see: (a) P. J. Campos, J. Arranz, M. A. Rodríguez,
Tetrahedron Lett. 1997, 38, 8397–8400; (b) I. Papoutsis, S. Spyroudis,
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10.1002/anie.201811717
Angewandte Chemie International Edition
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James R. Walker‡, Jeffrey E. Merit‡,
Rhiannon Thomas-Tran, Doris T. Y.
Tang, J. Du Bois*
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Divergent Synthesis of Natural
Derivatives of (+)-Saxitoxin Including
11-Saxitoxinethanoic acid
A synthetic strategy that enables access to four naturally occurring guanidinium
toxins, including saxitoxin, decarbamoyl saxitoxin, C13-acetoxy saxitoxin, and C11-
saxitoxinethanoic acid, is highlighted.
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